Боль и стресс у новорожденных

University of Louisville School of Medicine, Kosair Children's Hospital, Louisville, KYAsociaţia Internaţională pentru Studiul Durerii a definit în 1979 conceptul de durere ca „un răspuns senzorial şi emoţional neplăcut asociat cu vătămările prezente sau potenţiale ale ţesuturilor, sau descrise în termen de astfel de vătămări”. Sugarii şi fetuşii au capacitatea de a percepe durerea. Substraturile neuroanatomic, neurofiziologic şi neurochimic pentru perceperea durerii se dezvoltă începând de la mijlocul perioadei de gestaţie şi continuă să se dezvolte în perioada tardivă de gestaţie şi în copilărie. Reacţiile la durere a sugarilor născuţi în termen şi prematuri sunt atât fiziologice cât şi comportamentale. Expunerea la dureri prelungite sau severe poate creşte cazurile morbidităţii neonatale prin distrugerea celulelor neuronale. Are loc stimularea celulelor neuronale mediată de receptorul N-metil-D-aspartat (NMDA), cu aflux de calciu. Are loc apoptoza neuronală consolidată, potenţial din cauza separării materne sau a factorilor de stres metabolic. Controlul adecvat al durerii poate atenua unele dintre aceste efecte. Anand şi Hickey4 descriu schimbările de comportament asociate cu durerea şi le-au împărţit în patru categorii generale: reacţie motorie simplă, expresii faciale, plânsul şi reacţiile complexe de comportament. Severitatea durerii şi a efectelor analgezicilor poate fi evaluată la nou-născuţi cu ajutorul mijloacelor confirmate. Disponibil în unitatea de terapie intensivă este Profilul durerii la nou-născutul prematur (PIPP), iar în sectiile de îngrijire neonatală: Scorul durerii comportamentale (BPS) sau Nivelul de durere la nou-născuţi şi sugari (NIPS) pentru a evalua durerea pre- şi post-intervenţională. Între anii 1985-1992 KJS Anand şi Asociaţii a publicat literatură radicală care a relevat siguranţa relativă a agenţilor de anestezie şi rezultatele bune la copii şi adolescenţi supuşi unei intervenţii chirurgicale cu anestezie. După aceste publicaţii seminale, cercetările în domeniul durerii la nou-născuţi, atât clinice, cât şi cele ştiinţifice de bază, s-au extins. Recomandările curente ale Academiei Americane de Pediatrie (AAP) Comitetul asupra fătului şi nou-născutului (COFN) a extins ghidul pentru evaluarea şi gestionarea durerii şi stresului la nou-născuţi. Evaluarea ar trebui să urmeze următoarele: Îngrijitorii trebui instruiţi pentru a evalua durerea la nou-născuţi prin utilizarea de instrumente multidimensionale Nou-născuţii trebuie evaluaţi în mod curent până/după proceduri Folosirea gradaţiei durerii ajută la ghidarea îngrijitorilor în asigurarea unei alienări efi cace a durerii Principiul trebuie să minimizeze cât mai mult posibil numărul de subminări dureroase în îngrijire Să utilizeze anestezice topice pentru venipuncţie, puncţie lombară şi picurătoare Nu se recomandă utilizarea de rutină a picăturilor de morfină, fentanilă sau midazolam la pacienţii cronici ventilaţi Să folosească zaharoza/glucoza orală şi alte metode non-farmacologice de reducere a durerii: aspiraţia non-nutritivă, îngrijirea stil cangur, întinderea facilitată, înfăşarea şi îngrijirea de dezvoltare Există publicate câteva studii clinice randomizate controlate privind gestionarea durerii la nou-născuţi. Studiul NEOPAIN a evaluat analgezia cu perfuzie de morfină de până la 14 zile la sugarii prematuri ventilaţi. Dozele de morfină folosite în acest studiu au scăzut semnele clinice de durere, dar au fost asociate cu efecte adverse semnificative la sugari prematuri ventilaţi. Astfel, studiul ar sugera ca morfina să fie utilizată numai la sugarii normotensivi. Pentru procedurile minim-invazive: Soluţie de zaharoză 24% (0,5-1,5 ml) Proceduri invazive: Narcotice, inclusiv morfina, fentanila şi sedative Intubaţia: Fentanilă (1 mcg/kg pînă la 3 mcg/kg), pentru o procedură; În cazul în care sugarul rămîne intubat şi este nevoie de analgezie, se va folosi o perfuzie continuă de fentanilă sau morfină. Durerea preoperatorie: 1) Sugarii se vor premedica cu fentanilă cu o oră înainte de transferul în sala chirurgicală în cazul în care sunt intubaţi; altfel, aceasta se va administra la SAU înainte de intubaţie; 2) Pentru revenire – dacă este necesar, se fa folosi nalaxon (Narcan 0,1 mg/kg) pentru tratarea sugarilor cu efecte adverse excesive în urma administrării de opoide; poate fititrat pentru a păstra careva efecte analgezice.В 1979 г. Международная Ассоциация по изучению боли предложила следующее научное определение: «Боль — это неприятное ощущение и эмоциональное переживание, связанное с текущим или потенциальным ткане- вым повреждением или описываемое в терминах такого повреждения». Плод и новорожденные обладают способностью воспринимать боль. Нейроанатомические, нейрофизио- логические и нейрохимические структуры, отвечающие за восприятие боли, развиваются, начиная с середины беременности, продолжая развиваться на поздних сроках беременности и в детстве. Реакция на боль у доношенных и недоношенных детей носят физиологический и поведенческий характер. Длительное воздействие боли, а так же сильной боли, может увеличить случаи заболеваемости новорожден- ных посредством разрушения нервных клеток. Стимуляция нервных клеток происходит за счет рецептор- опосредованного N-метил-D-аспартата (NMDA), а так же за счет притока кальция. Имеет место обширный апоптоз нейронов, вероятно возникающий в связи с отлучением от мамы или метаболическим стрессом. Адекватный контроль боли может облегчить некоторые из этих эффектов. Ананд и Хики4 описывают поведенческие изменения, связанные с болью, которые были подразделены ими на четыре основные категории: простая двигательная реакция, мимика, плач и сложные поведенческие реак- ции. Тяжесть боли и обезболивающего эффекта у детей могут быть оценены с помощью подтвержденных инструментов. В Отделении Интенсивной Терапии в наличии имеется Профиль боли у недоношенных ново- рожденных (PIPP), а в Отделениях по уходу за новорожденными: Оценка поведенческой боли (BPS), или Уро- вень боли у новорожденных и грудных детей (NIPS) для оценки боли до и после вмешательств. Существует несколько опубликованных рандомизированных контролируемых исследований о лечении боли у новорожденных. Исследование NEOPAIN оценивало болеутоляющий эффект инфузий морфина в течение 14 дней у вентилируемых недоношенных новорожденных. Дозы морфина, используемых в данном исследовании, снизили клинические признаки боли, но привели к значительным побочным эффектам у вентилируемых недоно- шенных детей. Таким образом, исследование показало, что морфин следует использовать только у младенцев с нормальным артериальным давлением

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

PIF Genes Mediate the Effect of Sucrose on Seedling Growth Dynamics

As photoautotrophs, plants can use both the form and amount of fixed carbon as a measure of the light environment. In this study, we used a variety of approaches to elucidate the role of exogenous sucrose in modifying seedling growth dynamics. In addition to its known effects on germination, high-resolution temporal analysis revealed that sucrose could extend the number of days plants exhibited rapid hypocotyl elongation, leading to dramatic increases in ultimate seedling height. In addition, sucrose changed the timing of daily growth maxima, demonstrating that diel growth dynamics are more plastic than previously suspected. Sucrose-dependent growth promotion required function of multiple phytochrome-interacting factors (PIFs), and overexpression of PIF5 led to growth dynamics similar to plants exposed to sucrose. Consistent with this result, sucrose was found to increase levels of PIF5 protein. PIFs have well-established roles as integrators of response to light levels, time of day and phytohormone signaling. Our findings strongly suggest that carbon availability can modify the known photomorphogenetic signaling network

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

Do Trees Grow on Money? Auxin as the Currency of the Cellular Economy

Auxin plays a role in nearly every aspect of a plant's life. Signals from the developmental program, physiological status, and encounters with other organisms all converge on the auxin pathway. The molecular mechanisms facilitating these interactions are diverse; yet, common themes emerge. Auxin can be regulated by modulating rates of biosynthesis, conjugation, and transport, as well as sensitivity of a cell to the auxin signal. In this article, we describe some well-studied examples of auxin's interactions with other pathways